PROGRESSION TO ANDROGEN INSENSITIVITY IN A NOVEL IN-VITRO MOUSE MODEL FOR PROSTATE-CANCER
PROGRESSION TO ANDROGEN INSENSITIVITY IN A NOVEL IN-VITRO MOUSE MODEL FOR PROSTATE-CANCER
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DOI：
10.1016/0960-0760(95)00001-g
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发表时间：
1995-05-01
影响因子：
4.1
通讯作者：
THOMPSON, TC
中科院分区：
文献类型：
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作者：
BALEY, PA;YOSHIDA, K;THOMPSON, TC
我们以前已经表明，ras和myc癌基因可以诱导低分化的小鼠前列腺癌在体内高频率（大于90%）使用近交系C57 BL/6小鼠在小鼠前列腺重建模型系统。为了研究这些癌的雄激素敏感性，我们已经开发了一种体外模型系统，其中包括正常泌尿生殖窦上皮细胞系（CUGE）和三个ras+myc转化的小鼠前列腺癌（RM-9，RM-1和RM-2）的细胞系。CUGE细胞，以及所有的前列腺癌细胞系，细胞角蛋白18 mRNA和细胞角蛋白特异性抗血清免疫反应阳性。三个早期传代癌细胞系中有两个是关于Zipras/myc 9逆转录病毒整合的克隆，如通过Southern印迹分析所确定的。然而，在无血清培养基中生长的CUGE细胞中未观察到睾酮（10 nM）的显著促有丝分裂作用，在类似条件下，2-在所有低传代前列腺癌细胞系中观察到细胞数的倍数增加。此外，在存在生长抑制水平的苏拉明（50 μ g/ml）的情况下，睾酮能够在癌细胞系中显著刺激生长。随着从低传代[20-25群体倍增（PD）]到高传代（75-100 PD）的进一步增殖，所有癌细胞系在存在和不存在睾酮的情况下均表现出增加的和相似的生长速率。这些细胞系在培养物中多次传代（>150 PD）期间从睾酮响应性生长过渡到响应性降低期间保持稳定的雄激素受体数量和结合动力学。总体而言，我们的研究表明，通过雄激素敏感型向不敏感型的转变，结合睾酮的能力得到稳定维持，并提高了雄激素敏感性在整个进展过程中持续存在但被自分泌途径的获得所掩盖的可能性。
We have shown previously that the ras and myc oncogenes can induce poorly differentiated mouse prostate carcinomas in vivo with high frequency (greater than 90%) using inbred C57BL/6 mice in the mouse prostate reconstitution model system. To study the androgen sensitivity of these carcinomas, we have developed an in vitro model system which includes a cell line from normal urogenital sinus epithelium (CUGE) and cell lines from three ras+myc transformed mouse prostate carcinomas (RM-9, RM-1, and RM-2). CUGE cells, as well as all prostate carcinoma cell lines, were positive for cytokeratin 18 mRNA and immunoreactive to cytokeratin-specific antiserum. Two out of three of the early passage carcinoma cell lines were clonal with respect to Zipras/myc 9 retrovirus integration as determined by Southern blot analysis. Whereas significant mitogenic effects of testosterone (10 nM) were not seen in CUGE cells grown in serum-free medium, under similar conditions approx. 2-fold increases in cell number were seen in all low passage prostate carcinoma cell lines. Also, in the presence of growth inhibitory levels of suramin (50 mu g/ml), testosterone was capable of significant growth stimulation in the carcinoma cell lines. With further propagation from low passage [20-25 population doublings (PD)] to high passage (75-100 PD), all carcinoma cell lines demonstrated increased and similar growth rate in the presence and absence of testosterone. These cell lines maintained stable androgen receptor numbers and binding kinetics during the transition from testosterone-responsive growth to reduced responsivity over multiple passages in culture (>150 PD). Overall, our studies indicate that the capacity to bind testosterone is stably maintained through the transition of the androgen-sensitive to insensitive phenotype and raise the possibility that androgen sensitivity can persist throughout progression but is masked by the acquisition of autocrine pathways.